Thrombospondin 1 protects pancreatic beta-cells from lipotoxicity via the PERK-NRF2 pathway
2016 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 23, no 12, 1995-2006 p.Article in journal (Refereed) Published
The failure of beta-cells has a central role in the pathogenesis of type 2 diabetes, and the identification of novel approaches to improve functional beta-cell mass is essential to prevent/revert the disease. Here we show a critical novel role for thrombospondin 1 (THBS1) in beta-cell survival during lipotoxic stress in rat, mouse and human models. THBS1 acts from within the endoplasmic reticulum to activate PERK and NRF2 and induce a protective antioxidant defense response against palmitate. Prolonged palmitate exposure causes THBS1 degradation, oxidative stress, activation of JNK and upregulation of PUMA, culminating in beta-cell death. These findings shed light on the mechanisms leading to beta-cell failure during metabolic stress and point to THBS1 as an interesting therapeutic target to prevent oxidative stress in type 2 diabetes.
Place, publisher, year, edition, pages
2016. Vol. 23, no 12, 1995-2006 p.
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-311482DOI: 10.1038/cdd.2016.89ISI: 000388973000013PubMedID: 27588705OAI: oai:DiVA.org:uu-311482DiVA: diva2:1060582
FunderEU, European Research Council, 667191